Prions Evolve, Scripps Florida Study Finds

Prions, those mysterious bits of protein that can cause
Creutzfeldt-Jakob
disease
,
kuru
, mad
cow disease and scrapie, evolve according to Darwin's theory of
evolution by natural selection. Researchers at The Scripps Research
Institute's branch in Jupiter, Florida,
announced
the findings
in the Dec. 31 online issue of the journal
Science.

Prions are proteins that we all have. Prion diseases are caused
by mistakes in folding these proteins. While DNA codes for making
proteins, they form extremely intricate 3D structures that help
determine their function. A misfolded protein, caused by some
post-transcription error, can catalyze formation of other proteins,
and the end result is prion disease. In other words, prion disease
are not genetic diseases, although genes play a role in
vulnerability.

Prions can evolve drug resistance and other beneficial mutations
(from the prion's point of view, at least), like living things do,
the study found. Prion diseases are remorseless and, as far as we
know, 100 percent fatal, as the victims' brains are chewed away by
the deadly protein.

It shouldn't be surprising that Darwinian evolution be found in
prions, which after all are organic molecules. Darwin's insights
have penetrated far afield from his original observation of
evolution in whole organisms. Darwinian evolution has been used to
design
chemicals
from mutation and directed selection of molecules,
computerized
and even used to
create
software programs
.

"On the face of it, you have exactly the same process of
mutation and adaptive change in prions as you see in viruses," said
Charles
Weissmann
, M.D., Ph.D., the head of Scripps Florida's
Department of Infectology, who led the study. "This means that this
pattern of Darwinian evolution appears to be universally active. In
viruses, mutation is linked to changes in nucleic acid sequence
that leads to resistance. Now, this adaptability has moved one
level down – to prions and protein folding – and it's clear that
you do not need nucleic acid for the process of
evolution."

"In the first part of the study, Weissmann and his
colleagues transferred prion populations from infected brain cells
to culture cells. When transplanted, cell-adapted prions developed
and out-competed their brain-adapted counterparts, confirming
prions' ability to adapt to new surroundings, a hallmark of
Darwinian evolution. When returned to brain, brain-adapted prions
again took over the population.

"To confirm the findings and to explore the issue of
evolution of drug resistance, Weissmann and his colleagues used the
drug swainsonine or swa, which is found in plants and fungi, and
has been shown to inhibit certain prion strains. In cultures where
the drug was present, the team found that a drug-resistant
sub-strain of prion evolved to become predominant. When the drug
was withdrawn, the sub-strain that was susceptible to swainsonine
again grew to become the major component of the
population.

"Weissmann notes that the findings have implications for the
development of therapeutic targets for prion disease. Instead of
developing drugs to target abnormal proteins, it could be more
efficient to try to limit the supply of normally produced prions –
in essence, reducing the amount of fuel being fed into the fire.
Weissmann and his colleagues have shown some 15 years ago that
genetically engineered mice devoid of the normal prion protein
develop and function quite normally (and are resistant to prion
disease!). . .